Hepatitis B, hepatitis C, and mortality among HIV-positive individuals.

OBJECTIVES: To compare rates of all-cause, liver-related, and AIDS-related mortality among individuals who are HIV-monoinfected with those coinfected with HIV and hepatitis B (HBV) and/or hepatitis C (HCV) viruses. DESIGN: An ongoing observational cohort study collating routinely collected clinical data on HIV-positive individuals attending for care at HIV treatment centres throughout the United Kingdom. METHODS: Individuals were included if they had been seen for care from 2004 onwards and had tested for HBV and HCV. Crude mortality rates (all cause, liver related, and AIDS related) were calculated among HIV-monoinfected individuals and those coinfected with HIV, HBV, and/or HCV. Poisson regression was used to adjust for confounding factors, identify independent predictors of mortality, and estimate the impact of hepatitis coinfection on mortality in this cohort. RESULTS: Among 25 486 HIV-positive individuals, with a median follow-up 4.5 years, HBV coinfection was significantly associated with increased all-cause and liver-related mortality in multivariable analyses: adjusted rate ratios (ARR) [95% confidence intervals (95% CI)] were 1.60 (1.28-2.00) and 10.42 (5.78-18.80), respectively. HCV coinfection was significantly associated with increased all-cause (ARR 1.43, 95% CI 1.15-1.76) and liver-related mortality (ARR 6.20, 95% CI 3.31-11.60). Neither HBV nor HCV coinfection were associated with increased AIDS-related mortality: ARRs (95% CI) 1.07 (0.63-1.83) and 0.40 (0.20-0.81), respectively. CONCLUSION: The increased rate of all-cause and liver-related mortality among hepatitis-coinfected individuals in this HIV-positive cohort highlights the need for primary prevention and access to effective hepatitis treatment for HIV-positive individuals.

Can Hepatitis C Virus Antigen Testing Replace Ribonucleic Acid Polymearse Chain Reaction Analysis for Detecting Hepatitis C Virus? A Systematic Review.

The complexity and cost of current diagnostics for hepatitis C virus (HCV) may act as a prevention to the scale-up of treatment in the developing world. Currently, ribonucleic acid (RNA)-polymerase chain reaction tests are the gold standard. However, there is potential for the use of simpler and cheaper antigen tests to confirm HCV infection in different clinical settings. We evaluated the sensitivity and specificity of antigen assays. This was compared with the reference-standard RNA assays. A subanalysis also assessed Architect core antigen test, which is the only commercially available antigen test on the market. In 24 datasets, evaluating HCV-antigen assays in 8136 samples, the percentage of HCV-antigen positive, HCV-RNA negative was 0.57%. The percentage HCV-antigen negative, HCV-RNA positive was 3.52%. There is strong evidence that antigen detection performs as well as RNA-based assays for HCV management. The use of antigen tests could improve access to HCV care in underresourced healthcare settings.

Next-generation sequencing sheds light on the natural history of hepatitis C infection in patients who fail treatment.

UNLABELLED: High rates of sexually transmitted infection and reinfection with hepatitis C virus (HCV) have recently been reported in human immunodeficiency virus (HIV)-infected men who have sex with men and reinfection has also been described in monoinfected injecting drug users. The diagnosis of reinfection has traditionally been based on direct Sanger sequencing of samples pre- and posttreatment, but not on more sensitive deep sequencing techniques. We studied viral quasispecies dynamics in patients who failed standard of care therapy in a high-risk HIV-infected cohort of patients with early HCV infection to determine whether treatment failure was associated with reinfection or recrudescence of preexisting infection. Paired sequences (pre- and posttreatment) were analyzed. The HCV E2 hypervariable region-1 was amplified using nested reverse-transcription polymerase chain reaction (RT-PCR) with indexed genotype-specific primers and the same products were sequenced using both Sanger and 454 pyrosequencing approaches. Of 99 HIV-infected patients with acute HCV treated with 24-48 weeks of pegylated interferon alpha and ribavirin, 15 failed to achieve a sustained virological response (six relapsed, six had a null response, and three had a partial response). Using direct sequencing, 10/15 patients (66%) had evidence of a previously undetected strain posttreatment; in many studies, this is interpreted as reinfection. However, pyrosequencing revealed that 15/15 (100%) of patients had evidence of persisting infection; 6/15 (40%) patients had evidence of a previously undetected variant present in the posttreatment sample in addition to a variant that was detected at baseline. This could represent superinfection or a limitation of the sensitivity of pyrosequencing. CONCLUSION: In this high-risk group, the emergence of new viral strains following treatment failure is most commonly associated with emerging dominance of preexisting minority variants rather than reinfection. Superinfection may occur in this cohort but reinfection is overestimated by Sanger sequencing.

Reversible hepatic decompensation following cessation of antiretroviral therapy in a patient with HIV and hepatitis C co-infection.

We report the case of 47-year-old man with HIV and hepatitis C virus-associated cirrhosis who, following discontinuation of his antiretroviral therapy (ART), rapidly developed hepatic decompensation. On restarting his ART there was a noticeable improvement in his liver function, which was attributed to regaining good HIV virus control. Further data on the effects of restarting ART after ART cessation-associated hepatic decompensation are needed.

Natural NS3 resistance polymorphisms occur frequently prior to treatment in HIV-positive patients with acute hepatitis C.

NS3 protease inhibitors are set to improve sustained virological response rates in HIV-positive patients with hepatitis C. We measured the prevalence of natural resistance polymorphisms in 38 acutely infected treatment-naive patients using direct and deep sequencing. Twenty six percent of patients (10/38) had a majority variant resistance mutation (in order of frequency; Q80K - 16%, V36M - 5%, T54S - 3%, V55A - 3%, and D168A - 3%). Low-frequency mutations were detected in all samples. Further studies are required to determine threshold levels associated with treatment failure.

C-reactive protein is a useful predictor of metronidazole treatment failure in mild-to-moderate Clostridium difficile infection.

OBJECTIVE: To assess the ability of C-reactive (CRP) protein, against the other commonly used metrics, to predict metronidazole treatment failure in Clostridium difficile infection. METHODS: We retrospectively reviewed the case notes of 65 patients with C. difficile infection initially treated with metronidazole. Patients were grouped on the basis of outcome: those who responded to metronidazole within 6 days (cut-off as used by previous authors) versus those who required vancomycin. Individual predictor variables were examined between groups (using a t-test, Kruskal-Wallis test, or Fisher's exact test), and the strength of associations was assessed by logistic regression. RESULTS: Of the 65 patients reviewed, 48 (74%) resolved with metronidazole alone. Regression analysis found that (CRP) white cell count and creatinine levels were significantly different across the metronidazole success/failure groups (P<0.01, P=0.01 and P=0.03, respectively). CONCLUSION: (CRP) is a useful predictor of metronidazole treatment failure in mild-to-moderate C. difficile infection.

Hepatitis B virus infection in HIV-positive individuals in the UK collaborative HIV cohort (UK CHIC) study.

BACKGROUND: Hepatitis B virus (HBV) infection is an increasingly important cause of morbidity and mortality in HIV-infected adults. This study aimed to determine the prevalence and incidence of HBV in the UK CHIC Study, a multicentre observational cohort. METHODS AND FINDINGS: 12 HIV treatment centres were included. Of 37,331 patients, 27,450 had at least one test (HBsAg, anti-HBs or anti-HBc) result post-1996 available. 16,043 were white, 8,130 black and 3,277 other ethnicity. Route of exposure was homosexual sex 15,223 males, heterosexual sex 3,258 males and 5,384 females, injecting drug use 862 and other 2,723. The main outcome measures used were the cumulative prevalence and the incidence of HBV coinfection. HBV susceptible patients were followed up until HBsAg and/or anti-HBc seroconversion incident infection, evidence of vaccination or last visit. Poisson regression was used to determine associated factors. 25,973 had at least one HBsAg test result. Participants with HBsAg results were typically MSM (57%) and white (59%) (similar to the cohort as a whole). The cumulative prevalence of detectable HBsAg was 6.9% (6.6 to 7.2%). Among the 3,379 initially HBV-susceptible patients, the incidence of HBV infection was 1.7 (1.5 to 1.9)/100 person-years. Factors associated with incident infection were older age and IDU. The main limitation of the study was that 30% of participants did not have any HBsAg results available. However baseline characteristics of those with results did not differ from those of the whole cohort. Efforts are on-going to improve data collection. CONCLUSIONS: The prevalence of HBV in UK CHIC is in line with estimates from other studies and low by international standards. Incident infection continued to occur even after entry to the cohort, emphasising the need to ensure early vaccination.

Acute HCV/HIV coinfection is associated with cognitive dysfunction and cerebral metabolite disturbance, but not increased microglial cell activation.

BACKGROUND: Microglial cell activation and cerebral function impairment are described in both chronic hepatitis C viral (HCV) and Human-Immune-Deficiency viral (HIV) infections. The aim of this study was to investigate the effect of acute HCV infection upon cerebral function and microglial cell activation in HIV-infected individuals. METHODS: A case-control study was conducted. Subjects with acute HCV and chronic HIV coinfection (aHCV) were compared to matched controls with chronic HIV monoinfection (HIVmono). aHCV was defined as a new positive plasma HCV RNA within 12 months of a negative RNA test. Subjects underwent neuro-cognitive testing (NCT), cerebral proton magnetic resonance spectroscopy ((1)H-MRS) and positron emission tomography (PET) using a (11)C-radiolabeled ligand (PK11195), which is highly specific for translocator protein 18 kDA receptors on activated microglial cells. Differences between cases and controls were assessed using linear regression modelling. RESULTS: Twenty-four aHCV cases completed NCT and (1)H-MRS, 8 underwent PET. Of 57 HIVmono controls completing NCT, 12 underwent (1)H-MRS and 8 PET. Subjects with aHCV demonstrated on NCT, significantly poorer executive function (mean (SD) error rate 26.50(17.87) versus 19.09(8.12), p = 0.001) and on (1)H-MRS increased myo-inositol/creatine ratios (mI/Cr, a marker of cerebral inflammation) in the basal ganglia (ratio of 0.71(0.22) versus 0.55(0.23), p = 0.03), compared to subjects with HIVmono. On PET imaging, no difference in (11)C-PK11195 binding potential (BP) was observed between study groups (p>0.10 all cerebral locations), however lower BPs were associated with combination antiretroviral therapy (cART) use in the parietal (p = 0.01) and frontal (p = 0.03) cerebral locations. DISCUSSION: Poorer cognitive performance and disturbance of cerebral metabolites are observed in subjects with aHC,V compared to subjects with HIVmono. Higher (11)C-PK11195 BP was not observed in subjects with aHCV, but was observed in subjects not on cART.